Tag: Rectal Cancer

Management of Locally Advanced Rectal Cancer: ASCO Guideline Clinical Insights

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SUMMARY: The American Cancer Society estimates that 46,950 new cases of rectal cancer will be diagnosed in the US in 2025. Based on the information from the SEER database, the 5-year relative survival rates for rectal cancer all SEER stages combined is 67%.

The American Society of Clinical Oncology (ASCO) in 2024 published a guideline on treatment of locally advanced rectal cancer following a systematic review of research from 2013 to 2023. The systematic review included data from 12 randomized controlled trials, 2 systematic reviews, and 1 nonrandomized study.

The ASCO recommendations encouraged patients with MicroSatellite Stable (MSS) or proficient MisMatch Repair (MMR) locally advanced rectal cancer who have undergone assessment with dedicated rectal sequence pelvic MRI to consider Total Neoadjuvant Therapy (TNT) as initial treatment, for tumors in the lower rectum. They also encouraged those who are at a higher risk of local or distant metastases (T4, extramural vascular invasion and/or tumor deposits, threatened mesorectal fascia or intersphinteric plane and/or not eligible for sphincter sparing surgery, to consider TNT. For patients receiving TNT, long course chemoradiation is preferred, followed by chemotherapy consolidation prior to surgery.

Patients who do not present with high-risk factors (upper and middle rectal cancer and more than 5 mm of extramural invasion) are eligible to receive neoadjuvant FOLFOX chemotherapy, with selective ChemoRadiation Therapy (CRT) when extent of tumor response to chemotherapy is deemed insufficient.

Nonoperative management may be offered instead of total mesorectal excision for patients who demonstrate a clinical Complete Response to neoadjuvant therapy.

Immunotherapy is the recommended treatment for patients with tumors presenting with MicroSatellite Instability-High (MSI-H) or MisMatch Repair (MMR)-deficient disease.

The additional information provided below by ASCO is meant to addresses some of the questions that clinicians may face as they implement the recommendations into clinical practice.

Which Patients Are Included in the ASCO Guideline for Locally Advanced Rectal Cancer?
The ASCO guideline for locally advanced rectal cancer includes patients with T3 or T4 and/or node-positive disease. While T3 tumors with MRI-assessed extramural invasion ≤5 mm generally have better outcomes, the guideline classifies all low T3 rectal tumors, regardless of depth of invasion, as higher risk and includes them due to their increased recurrence risk. Patients with favorable T3 features may be addressed in a future guideline for early-stage rectal cancer.

What Is the Extent of Tumor Response Required for Omission of Radiation, That Is, Delivery of FOLFOX (Fluorouracil, Leucovorin, and Oxaliplatin) Chemotherapy Alone, for Patients with Locally Advanced Rectal Cancer?
This question applies to patients similar to those enrolled in the PROSPECT trial—specifically, individuals with T2 or T3 rectal tumors situated at least 3 mm from the circumferential resection margin, with no more than three involved pelvic lymph nodes, and eligible for sphincter-sparing surgery. In the trial, a tumor area reduction of at least 20% was considered an adequate response to potentially omit radiation therapy. However, it’s important to note that some lower-risk patients from the study fall outside the scope of the current ASCO guidelines for locally advanced rectal cancer.

What Is the Balance of Benefits and Harms in the PROSPECT Trial of FOLFOX with Selective Chemoradiation Versus Chemoradiation Alone?
Neoadjuvant chemoradiation (CRT) for rectal cancer has historically been associated with long-term bowel, bladder, and sexual dysfunction in approximately 14% of patients. In light of this, the PROSPECT trial explored a de-escalation approach to potentially reduce toxicity by omitting routine pelvic radiation in select patients with mid-rectal tumors that do not involve the mesorectal fascia.

This phase III noninferiority trial demonstrated comparable Disease-Free Survival, Overall Survival, and local recurrence between patients treated with neoadjuvant FOLFOX (infusional 5-FU, leucovorin, and oxaliplatin) and those who received standard CRT with 5-FU. With efficacy outcomes being similar, patient safety and quality of life became central in guiding treatment choices.

Clinician-reported Adverse Events (AE) of Grade 3 or more were more common with FOLFOX (41.0%) compared to CRT (22.8%), with neutropenia, pain, and hypertension being the most frequent in the FOLFOX group. In the CRT group, common severe AEs included lymphopenia, diarrhea, and hypertension.

Regarding neuropathy, FOLFOX was associated with a higher rate pre-surgery (19% vs 5%) but showed comparable rates to CRT at 12 and 18 months postoperatively. Patient-reported outcomes revealed that while both groups experienced significant symptoms during treatment (e.g., fatigue, appetite loss, neuropathy, diarrhea), most severe symptoms resolved by 12 months post-surgery.

Sexual function, particularly among men and women in the CRT group, was more negatively impacted at 12 months, but differences between groups diminished by 24 months. Health-Related Quality of Life (HRQOL) was similar across both treatment arms throughout the follow-up period.

Treatment decisions may also be influenced by individual concerns: for example, younger women concerned about fertility might prefer chemotherapy alone, while those seeking to avoid long-term neuropathy might favor CRT. Surgical outcomes, including ostomy rates, also play a role. While data from the PROSPECT trial on surgical outcomes are forthcoming, similar trials (e.g., CONVERT) reported a lower rate of preventive ileostomy with neoadjuvant chemotherapy compared to CRT.

What Is the Timing of Assessment for Clinical Complete Response and Potential Nonoperative Management Following Total Neoadjuvant Therapy?
Although this topic was not formally evaluated in the ASCO guideline, the Expert Panel generally supported the assessment timeline used in the OPRA phase II trial, which evaluated clinical Complete Response approximately 8 weeks (±4 weeks) after completing total neoadjuvant therapy (TNT). Panelists noted that if radiation is given first in the TNT sequence, waiting an additional 8 weeks after chemotherapy might lead to an overly long treatment-free period. In such cases, an earlier response assessment may be appropriate. If the initial evaluation shows a near-Complete Response, reassessment within 8 weeks is advised to monitor for full clinical response and consider nonoperative management, as being studied in the ongoing JANUS trial comparing doublet and triplet consolidation chemotherapy.

What Tools Should Be Used in the Assessment of Patients Who Are Participating in NOM?
This guidance is based on the follow-up procedures used in the OPRA trial for NonOperative Management (NOM) of locally advanced rectal cancer. Patients underwent digital rectal exams and flexible sigmoidoscopy every 4 months during the first 2 years after initial response assessment, then every 6 months for the next 3 years. Rectal MRI was performed at least every 6 months for the first 2 years, with less frequent imaging afterward. If imaging or endoscopy showed signs of regrowth or a decline in response, patients exited the NOM protocol and were referred for surgery. Routine biopsies of the tumor site were not required. Annual CT scans of the chest, abdomen, and pelvis were conducted for all patients.

Does Circulating Tumor DNA Have A Role in the Assessment of Response for Patients Who Have Undergone Neoadjuvant Therapy for Locally Advanced Rectal Cancer?
Currently, there is not enough evidence to support the use of circulating tumor DNA (ctDNA) in predicting treatment response for patients with locally advanced rectal cancer. Ongoing research in this area will be reviewed for potential inclusion in future updates to the ASCO guideline.

Should Endorectal Ultrasonography And/or Computed Tomography Be Used to Assess Locally Advanced Rectal Cancer When MRI Is Not Available?
Traditionally, Endorectal UltraSound (EUS) and sometimes CT scans have been used to evaluate rectal cancer. However, high-resolution MRI provides a more accurate assessment of tumor invasion into the MesoRectal Fascia (MRF). While MRI might not be accessible in all settings, no validated alternative imaging method is currently recommended in this guideline. In cases where MRI is not feasible, EUS and CT may be used, though they do not offer complete tumor staging.

Management of Locally Advanced Rectal Cancer: ASCO Guideline Clinical Insights. Scott AJ, Kennedy EB, Berlin J, et al. JCO Oncol Pract. 2025 Mar;21:281-286.

BREAKWATER Trial Establishes Encorafenib Combination with Cetuximab Plus mFOLFOX6 as a First-Line Standard for BRAF V600E–Mutated mCRC

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SUMMARY: Colorectal cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 154,270 new cases of CRC will be diagnosed in the United States in 2025 and about 52,900 patients will die of the disease. The lifetime risk of developing CRC is about 1 in 23.

Advanced colon cancer is often incurable and standard chemotherapy when combined with anti EGFR (Epidermal Growth Factor Receptor) targeted monoclonal antibodies such as Panitumumab (VECTIBIX®) and Cetuximab (ERBITUX®), as well as anti VEGF agent Bevacizumab (AVASTIN®), have demonstrated improvement in Progression Free Survival (PFS) and Overall Survival (OS). The benefit with anti EGFR agents however is only demonstrable in patients with metastatic CRC (mCRC) whose tumors do not harbor KRAS mutations in codons 12 and 13 of exon 2 (KRAS Wild Type). It is now also clear that even among the KRAS Wild Type patient group about 15-20% have other rare mutations such as NRAS and BRAF mutations, which confer resistance to anti EGFR agents. Patients with stage IV colorectal cancer are now routinely analyzed for extended RAS and BRAF mutations. KRAS mutations are predictive of resistance to EGFR targeted therapy.

BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. The BRAF V600E mutations results in constitutive activation of the MAP kinase pathway. Inhibiting BRAF can transiently reduce MAP kinase signaling. However, this can result in feedback upregulation of EGFR signaling pathway, which can then reactivate the MAP kinase pathway. This aberrant signaling can be blocked by dual inhibition of both BRAF and EGFR. It should be noted that BRAF V600E-mutated CRC is inherently less sensitive to BRAF inhibition than Malignant Melanoma.

Encorafenib (BRAFTOVI®) is a BRAF inhibitor and has target binding characteristics that differ from other BRAF inhibitors such as Vemurafenib (ZELBORAF®) and Dabrafenib (TAFINLAR®), with a prolonged target dissociation half-life and higher potency. The FDA in 2020, approved Encorafenib in combination with Cetuximab for the treatment of adult patients with metastatic ColoRectal Cancer (mCRC) with a BRAF V600E mutation

Background and Unmet Need
BRAF V600E mutations are found in approximately 8-10% of metastatic CRC and are associated with aggressive tumor biology, poor prognosis, and limited response to conventional first-line therapies. These patients tend to have aggressive disease with a higher rate of peritoneal metastasis and do not respond well to standard treatment intervention. Approximately 20% of the BRAF-mutated population in the metastatic setting has MSI-High tumors, but MSI-High status does not confer protection to this patient group. Historically, patients with these mutations experienced shorter survival when treated with chemotherapy with or without biologics such as Bevacizumab, compared to their BRAF wild-type counterparts. While the BEACON CRC trial established the Encorafenib plus Cetuximab (EC) doublet as standard in the previously treated setting, the optimal first-line strategy remained undefined.

Design of the BREAKWATER Study
The Phase 3 BREAKWATER trial addressed this gap by evaluating first-line treatment with Encorafenib and Cetuximab, with or without chemotherapy, in patients with previously untreated BRAF V600E-mutated mCRC. Initially designed with three arms (1:1:1), EC: Encorafenib (300 mg PO QD) + Cetuximab (500 mg/m² IV q2w), EC + mFOLFOX6: As above + Oxaliplatin, Leucovorin, and 5-FU and Control/Standard of Care: mFOLFOX6, FOLFOXIRI, or CAPOX with or without Bevacizumab, the protocol was later amended to focus on the EC+mFOLFOX6 (N=236) versus Standard of Care comparison (N=243). The median age was 61 yrs and stratification was based on ECOG performance status and geographic region. Eligible patients had metastatic colorectal adenocarcinoma with measurable disease and a confirmed BRAF V600E mutation, but no prior systemic therapy for metastatic disease. The Primary endpoints included Progression-Free Survival (PFS) and Objective Response Rate (ORR). Secondary endpoints included Overall Survival (OS), Duration of Response (DoR) and Time to Response.

Efficacy Highlights
The results were compelling across both Primary endpoints (ORR and PFS), as well as key Secondary outcomes:

  • Objective Response Rate (ORR):
    EC+mFOLFOX6 achieved a confirmed ORR of 7%, compared with 37.4% in the Standard of Care arm (Odds Ratio, 2.44; P<0.001), with a median Time to Response of approximately 7 weeks. The median Duration of Response was 13.9 months and 10.8 months respectively
  • Progression-Free Survival (PFS):
    The median PFS was 8 months with EC+mFOLFOX6 versus 7.1 months with standard care (Hazard Ratio [HR] for progression or death, 0.53; P<0.001), representing a 47% reduction in risk.
  • Overall Survival (OS):
    Interim analysis demonstrated a median OS of 3 months with EC+mFOLFOX6, more than double the 15.1 months observed in the Standard of Care group (HR for death, 0.49; P<0.001). Twelve and 24 month survival rates favored the investigational arm (80.1% and 52.0%, respectively) over Standard of Care (66.0% and 29.0%).

Notably, survival outcomes with EC+mFOLFOX6 approached those historically seen in BRAF wild-type mCRC, underscoring the potential for targeted therapy to narrow the survival gap.

Subgroup and Secondary Analyses
Benefits of EC+mFOLFOX6 were consistent across prespecified subgroups, including patients with liver metastases or multi-organ involvement. Additionally, median second Progression-Free Survival was longer with EC+mFOLFOX6, reinforcing its value in delivering durable disease control.

Safety Profile
While the incidence of grade ≥3 adverse events was higher in the EC+mFOLFOX6 group (46.1%) compared to standard care (38.9%), toxicity was manageable, and treatment discontinuations remained relatively low. The safety profile was consistent with expectations for the individual agents, and chemotherapy dose reductions were not substantially increased.

Clinical Implications
These findings firmly establish EC+mFOLFOX6 as a new first-line standard for patients with BRAF V600E–mutated mCRC. The dual-targeted approach combined with chemotherapy offers significantly improved outcomes in a population long characterized by poor prognosis. The results also highlight the importance of early integration of targeted therapy, particularly encorafenib, into the treatment paradigm.

Next Steps in BRAF-Targeted Strategies
Although the EC doublet showed some activity, particularly in patients ineligible for chemotherapy, its efficacy was inferior to the triplet regimen. Enrollment into the EC-only arm was halted, and current exploration includes EC combined with FOLFIRI (ongoing in BREAKWATER cohort 3) and EC plus pembrolizumab in MSI-H/dMMR populations (SEAMARK trial).

Conclusion
The BREAKWATER trial demonstrated that first-line treatment with EC+mFOLFOX6 significantly improves Response Rates, Progression-Free Survival, and Overall Survival, compared to standard chemotherapy regimens, in BRAF V600E–mutated mCRC. This represents a transformative advance, closing the gap in outcomes between BRAF-mutated and wild-type mCRC, and setting a new benchmark in precision oncology.

Encorafenib, Cetuximab, and mFOLFOX6 in BRAF-Mutated Colorectal Cancer. Elez E,  Yoshino T,  Shen L, et al., for the BREAKWATER Trial Investigators. N Engl J Med 2025;392:2425-2437

OPDIVO® (Nivolumab) with YERVOY® (Ipilimumab)

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The FDA on April 8, 2025, approved OPDIVO® with YERVOY® for adult and pediatric patients 12 years of age and older with unresectable or metastatic MicroSatellite Instability-High (MSI-H) or MisMatch Repair deficient (dMMR) ColoRectal Cancer (CRC). The FDA also converted the accelerated approval to regular approval for single agent OPDIVO® for adult and pediatric patients 12 years of age and older with MSI-H or dMMR metastatic CRC, that has progressed following Fuoropyrimidine, Oxaliplatin, and Irinotecan. OPDIVO®  and YERVOY® are products of Bristol Myers Squibb Company.

Rising Incidence of Pancreatic and Colorectal Adenocarcinoma among Younger Populations

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SUMMARY: The American Cancer Society estimates that in 2025, about 67,440 people will be diagnosed with pancreatic cancer and 51,980 people will die of the disease. Detecting cancer at early stages can significantly increase survival rates and outcomes. Pancreatic Ductal AdenoCarcinoma (PDAC) is one of the most lethal malignancies, ranking among the leading causes of cancer-related mortality globally. A significant challenge in improving PDAC outcomes is its frequent diagnosis at an advanced stage, when therapeutic options are limited and prognosis is poor, with a 5-year survival rate of approximately 10%. Early detection is critical to expanding treatment possibilities and enhancing survival rates. Colorectal cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 154,270 new cases of CRC will be diagnosed in the United States in 2025 and about 52,900 patients will die of the disease. Even though the diagnosis of colorectal cancer in the US is dropping among people 65 years and older, the incidence has been rising in the younger age groups, with 12% of colorectal cancer cases diagnosed in people under age 50, leading to revisions in screening guidelines.

Study Objective
To provide an updated analysis of Annual Percentage Changes (APCs) in the incidence of pancreatic and colorectal adenocarcinoma across different age groups, focusing on younger populations, using data from the SEER database (2000–2021).

Methods
Data Source

  • SEER (Surveillance, Epidemiology, and End Results) database (22 registries, ~47.9% of US population)
  • Data updated through April 17, 2024

Study Design

  • Retrospective cohort study
  • Inclusion: Pancreatic and colorectal adenocarcinoma only
  • Exclusion: Rare pancreatic cancer subtypes (e.g., neuroendocrine tumors, mucinous cystadenocarcinoma)
  • The Rutgers University IRB exempted the study, and informed consent was not needed owing to the deidentified nature of the data.

Analysis

  • Yearly incidence rates per 100,000 population
  • Annual Percentage Changes (APCs) and 95% confidence intervals calculated for three age groups:
    • 15–34 years
    • 35–54 years
    • 55+ years

Results
Pancreatic Adenocarcinoma

  • Total cases (2000–2021): 275,273
    • 51.8% male, 87.1% aged ≥55 years
  • APC in 15–34 years: 4.35% (95% CI, 2.03–6.73)
  • APC in 35–54 years: 1.54% (95% CI, 1.18–1.90)
  • APC in 55+ years: 1.74% (95% CI, 1.59–1.89)

The APC for pancreatic adenocarcinoma in the group aged 15 to 34 year was statistically significantly higher than the APCs of 1.74 (P =0.007) for the group aged 55 years and older and 1.54 (P =0.004) for the group aged 35 to 54 years. The authors commented that the dramatic increase in the APC in the younger population suggests that close attention should be paid to this trend.

Colorectal Adenocarcinoma

  • Total cases: 1,215,200
    • 52.8% male, 80.4% aged ≥55 years
  • APC in 15–34 years: 1.75% (95% CI, 1.08–2.42)
  • APC in 35–54 years: 0.78% (95% CI, 0.51–1.06)
  • APC in 55+ years: -3.31% (95% CI, -3.54 to -3.08)

The APC for colorectal adenocarcinoma for the group aged 55 years and older was statistically significantly lower than the APCs for the group aged 15 to 34 years (P =0.001) and for the group aged 35 to 54 years (P =0.002). Most declines in colorectal cancer incidence was attributed to increased screening in older adults. Screening age was lowered from 50 to 45 years and may likely reduce future incidence in those aged 35–54.

Interpretation & Implications

Pancreatic Cancer

  • Though rare, pancreatic adenocarcinoma in young adults (15–34 years) is rising at an alarming rate.
  • Potential contributors: Smoking, alcohol, environmental exposures, though definitive causes remain unclear.
  • Clinician awareness is critical when evaluating younger patients with:
    • Abdominal pain
    • Weight loss
    • Anemia
    • Family history of pancreatic cancer

Clinical Insight: Historically, the above findings are not investigated in a young individual. It is therefore important to make sure a serious condition is not missed.

Colorectal Cancer

  • Increasing in younger groups, despite an overall declining trend.
  • This supports recent screening age revisions and highlights the need for vigilance in symptomatic young patients.

Limitations

  • SEER data covers ~47.9% of the U.S. population.
  • However, SEER is designed for accurate trend analysis and has reliable coding for common cancers like pancreatic and colorectal adenocarcinoma.
  • Restricting to adenocarcinoma improves the homogeneity and accuracy of the study.

Conclusions

  • Pancreatic adenocarcinoma incidence is rising in all age groups, especially in the youngest cohort (15–34 years).
  • Colorectal adenocarcinoma is increasing among younger individuals, while declining among those 55 and older.
  • Clinicians must heighten awareness of these trends and consider appropriate workups in symptomatic younger patients.

Key Takeaways

  • Pancreatic adenocarcinoma incidence rose >4% annually in individuals aged 15–34 years.
  • Colorectal adenocarcinoma also increased among patients aged 15–34 years.
  • Consider early imaging and endoscopic evaluations in symptomatic young adults.
  • Continue to support early screening efforts, especially for high-risk individuals.

Incidence of Pancreas and Colorectal Adenocarcinoma in the US. Bussetty A, Shen J, Benias PC, et al. JAMA Netw Open. 2025;8(4):e254682. doi:10.1001/jamanetworkopen.2025.4682

 

 

 

 

 

FDA Approves OPDIVO® Plus YERVOY® for Unresectable or Metastatic MSI-H/MMR Deficient Colorectal Cancer

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SUMMARY: The FDA on April 8, 2025, approved Nivolumab (OPDIVO®) with Ipilimumab (YERVOY®) for adult and pediatric patients 12 years of age and older with unresectable or metastatic MicroSatellite Instability-High (MSI-H) or MisMatch Repair deficient (dMMR) colorectal cancer (CRC). The FDA also converted the accelerated approval to regular approval for single agent Nivolumab for adult and pediatric patients 12 years of age and older with MSI-H or dMMR metastatic CRC, that has progressed following Fluoropyrimidine, Oxaliplatin, and Irinotecan.

Colorectal cancer is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 154,270 new cases of CRC will be diagnosed in the United States in 2025 and about 52,900 patients will die of the disease. The lifetime risk of developing CRC is about 1 in 23. The majority of CRC cases (about 75 %) are sporadic whereas the remaining 25 % of the patients have a family history of the disease. Only 5-6 % of patients with CRC with a family history background are due to inherited mutations in major CRC genes, while the rest are the result of accumulation of both genetic mutations and epigenetic modifications of several genes. Colorectal Cancer is a heterogeneous disease classified by its genetics, and even though the diagnosis of Colorectal Cancer in the US is dropping among people 65 years and older, the incidence has been rising in the younger age groups, with 12% of Colorectal Cancer cases diagnosed in people under age 50.

The DNA MisMatchRepair (MMR) system is responsible for molecular surveillance and works as an editing tool that identifies errors within the microsatellite regions of DNA and removes them. Defective MMR system leads to MSI (Micro Satellite Instability) and hypermutation, with the expression of tumor-specific neoantigens at the surface of cancer cells, triggering an enhanced antitumor immune response. MSI is therefore a hallmark of defective/deficient DNA MisMatchRepair (dMMR) system and occurs in 15% of all colorectal cancers. Defective MMR can be a sporadic or heritable event. Approximately 65% of the MSI high colon tumors are sporadic and when sporadic, the DNA MMR gene is MLH1. Defective MMR can manifest as a germline mutation occurring in MMR genes including MLH1, MSH2, MSH6 and PMS2. This produces Lynch Syndrome often called Hereditary Nonpolyposis Colorectal Carcinoma – HNPCC, an Autosomal Dominant disorder that is often associated with a high risk for Colorectal and Endometrial carcinoma, as well as several other malignancies including Ovary, Stomach, Small bowel, Hepatobiliary tract, Brain and Skin. MSI is a hallmark of Lynch Syndrome-associated cancers. MSI high tumors tend to have better outcomes and this has been attributed to the abundance of tumor infiltrating lymphocytes in these tumors from increase immunogenicity. These tumors therefore are susceptible to blockade with immune checkpoint inhibitors.

MSI testing is performed using a PCR or NGS based assay and MSI-High refers to instability at 2 or more of the 5 mononucleotide repeat markers and MSI-Low refers to instability at 1 of the 5 markers. Patients are considered Micro Satellite Stable (MSS) if no instability occurs. MSI-L and MSS are grouped together because MSI-L tumors are uncommon and behave similar to MSS tumors. Tumors considered MSI-H have deficiency of one or more of the DNA MMR genes. MMR gene deficiency can be detected by ImmunoHistoChemistry (IHC). NCCN Guidelines recommend MMR or MSI testing for all patients with a history of Colon or Rectal cancer. Unlike Colorectal and Endometrial cancer, where MSI-H/dMMR testing is routinely undertaken, the characterization of Lynch Syndrome across heterogeneous MSI-H/dMMR tumors is unknown.

Nivolumab is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, whereas Ipilimumab is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152). Blocking the Immune checkpoint proteins unleashes the T cells, resulting in T cell proliferation, activation and a therapeutic response.

The present FDA approval is based on CheckMate 8HW, which is an ongoing Phase III, multinational, open-label, randomized trial evaluating Nivolumab plus Ipilimumab as compared with Nivolumab alone or chemotherapy, in patients with MSI-H or dMMR metastatic CRC. In this study, patients with unresectable or mCRC and MSI-H/dMMR status by local testing who had received 0-1 prior line of therapy were randomly assigned in a 2:2:1 ratio to receive either Nivolumab monotherapy (N=353), Nivolumab plus Ipilimumab combination therapy (N=354), or the investigator’s choice of chemotherapy (mFOLFOX6 or FOLFIRI with or without Bevacizumab or Cetuximab (N=132). Patients who had previously received two or more prior lines of therapy for unresectable or metastatic disease were randomly assigned, in a 1:1 ratio, to receive Nivolumab plus Ipilimumab or Nivolumab alone. In the Nivolumab monotherapy arm, patients received Nivolumab 240 mg IV once every two weeks for six doses, followed by 480 mg IV every four weeks. In the Nivolumab plus Ipilimumab arm, patients were given Nivolumab 240 mg IV plus Ipilimumab 1mg/kg IV every three weeks for four doses, followed by Nivolumab 480 mg IV every four weeks. The median patient age was 64 years and tumor location was in the right colon in two thirds of the patients. Treatments continued until disease progression or unacceptable toxicity in all treatment groups or a maximum of 2 years. The dual Primary end points were Progression-Free Survival (PFS) as determined by Blinded Independent Central Review (BICR) comparing Nivolumab plus Ipilimumab to chemotherapy in the first-line therapy setting, and PFS comparing Nivolumab monotherapy to Nivolumab plus Ipilimumab across all lines of therapy, in patients with centrally confirmed MSI-H/dMMR metastatic CRC. At a median follow-up of 31.5 months the results from the prespecified interim analysis (the primary analysis) showed that the PFS outcomes were significantly better with Nivolumab plus Ipilimumab than with chemotherapy (HR=0.21; P<0.001).

The researchers herein reported the first results from the other dual Primary endpoint of PFS for Nivolumab plus Ipilimumab versus Nivolumab monotherapy across all lines of therapy in patients with centrally confirmed MSI-H/dMMR metastatic CRC. Of all the randomized patients 296 in the Nivolumab plus Ipilimumab group and 286 in the Nivolumab monotherapy group had centrally confirmed MSI-H/dMMR status. With a median follow-up of 47.0 months, Nivolumab plus Ipilimumab demonstrated clinically meaningful and statistically significant improvement in PFS by BICR versus Nivolumab monotherapy, with a median PFS Not Reached (NR) in the Nivolumab plus Ipilimumab group, compared to 39.3 months for those on Nivolumab monotherapy (HR=0.62; P= 0.0003). The PFS rates at 12, 24, and 36 months were higher in the Nivolumab plus Ipilimumab group at 76%, 71%, 68% versus 63%, 56%, 51% for Nivolumab monotherapy. The Objective Response Rate (ORR) was significantly higher with Nivolumab plus Ipilimumab at 71%, compared to 58% with Nivolumab alone (P=0.0011). No new safety concerns were identified.

It was concluded that the CheckMate 8HW study met its dual Primary endpoints, with Nivolumab plus Ipilimumab demonstrating a statistically significant and clinically meaningful improvement in PFS compared to Nivolumab monotherapy across all lines of therapy in MSI-H/dMMR metastatic CRC. Moreover, Nivolumab plus Ipilimumab was associated with higher ORR, confirming its potential as a new standard of care for patients with MSI-H/dMMR metastatic CRC. The CheckMate 8HW study is a pivotal contribution to the treatment landscape of MSI-H/dMMR metastatic Colorectal cancer, providing compelling evidence for the use of Nivolumab plus Ipilimumab in the first-line and beyond.

Nivolumab plus ipilimumab versus nivolumab in microsatellite instability-high metastatic colorectal cancer (CheckMate 8HW): a randomised, open-label, phase 3 trial. Andre T, Elez E, Lenz H-J, et al. The Lancet. 2025; 405:383-395

Late Breaking Abstract – 2025 ASCO GI Symposium: Circulating Tumor DNA (ctDNA) as a Predictive Biomarker for Celecoxib Benefit in Stage III Colon Cancer: Insights from CALGB/SWOG 80702

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SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 154,270 new cases of CRC will be diagnosed in the United States in 2025 and about 52,900 patients will die of the disease. The lifetime risk of developing CRC is about 1 in 23.

It is estimated that approximately 30% of patients with Stage II or III CRC and 60-70% of patients after oligometastatic resection experience recurrence. Adjuvant chemotherapy for patients with resected, locally advanced, node-positive (Stage III) colon cancer has been the standard of care since the 1990s. However, not all patients with Stage III disease benefit from adjuvant chemotherapy. In the IDEA trial, the absolute Disease Free Survival benefit of adjuvant chemotherapy for the lowest-risk Stage III group and the highest-risk group was 8% and 20%, respectively, suggesting that a substantial number of patients with low-risk Stage III cancer can safely forgo adjuvant chemotherapy or be considered for treatment de-escalation.

More recent data suggests that platelets may play a role in tumorigenesis as well, through the release of angiogenic and growth factors due to overexpression of Cyclooxygenase 2 (COX-2). Aspirin and COX-2 inhibitors such as Celecoxib have been associated with a reduced risk of colorectal polyps and cancer in observational and randomized studies.

The CALGB/SWOG 80702 is a randomized Phase III trial conducted to determine if the addition of Celecoxib to adjuvant chemotherapy with Fluorouracil, Leucovorin, and Oxaliplatin (FOLFOX) improves Disease-Free Survival (DFS) in patients with Stage III colon cancer. Patients were randomized to receive adjuvant FOLFOX (every 2 weeks) for 3 versus 6 months with or without 3 years of Celecoxib (400 mg orally daily; N=1263) versus placebo; N=1261). In this study, the addition of Celecoxib for 3 years to standard adjuvant chemotherapy did not significantly improve Disease-Free Survival (DFS).

The present analysis evaluated the prognostic and predictive value of circulating tumor DNA (ctDNA) in identifying a subpopulation of patients in the above study, who may potentially benefit from Celecoxib therapy. A subset of 1,011 patients from the CALGB/SWOG 80702 trial with adequate biospecimen availability was included in this analysis. ctDNA status was assessed using a tumor-informed, clinically validated 16-plex multiplex Polymerase Chain Reaction Next-Generation Sequencing (mPCR-NGS) assay (Signatera(TM), Natera, Inc.). Plasma samples were collected post-surgery and before the initiation of adjuvant chemotherapy. Survival outcomes, including DFS and Overall Survival (OS), were analyzed using Kaplan-Meier estimates and Cox proportional hazards models.

Results:

  • Of the 1,011 patients with ctDNA data, 189 (18.7%) tested ctDNA-positive.
  • ctDNA positivity correlated with male sex, advanced T stage, and N2 nodal disease.
  • Patients with detectable ctDNA had significantly worse outcomes:
    • DFS: Hazard Ratio (HR)=6.52; P<0.0001
    • OS: HR=6.28; P<0.0001
  • Three-year DFS rates were:
    • 6% in ctDNA-negative patients
    • 8% in ctDNA-positive patients
  • Celecoxib did not significantly impact DFS in ctDNA-negative patients (HR=0.75; P=0.095, 3-year DFS: 87.7% vs. 85.5%).
  • However, in ctDNA-positive patients, Celecoxib was associated with a notable improvement in DFS (HR=0.59; P=0.004, 3-year DFS: 44.1% vs. 26.6%).
  • OS trends mirrored those observed for DFS:
    • ctDNA-negative group: HR=0.86 (P=0.49) with Celecoxib versus placebo.
    • ctDNA-positive group: HR=0.63 (P=0.028) with Celecoxib versus placebo.
  • Multivariate analysis confirmed a statistically significant benefit of Celecoxib in ctDNA-positive patients.

Conclusion: ctDNA serves as a strong prognostic biomarker for both DFS and OS in Stage III colon cancer. Furthermore, ctDNA positivity appears to predict a significant therapeutic benefit from adjuvant Celecoxib, suggesting its potential role in stratifying patients for COX-2 inhibitor therapy. These findings highlight the utility of ctDNA assessment in guiding adjuvant treatment decisions and optimizing personalized therapeutic strategies in colon cancer.

Clinical Implications:

  • Post-surgical ctDNA testing can help identify patients at elevated risk of recurrence.
  • Celecoxib may offer a survival advantage for ctDNA-positive patients when used alongside standard FOLFOX chemotherapy.
  • Further research is warranted to elucidate the role of ctDNA-guided treatment in personalizing colon cancer therapy.

Prognostic and predictive role of circulating tumor DNA (ctDNA) in stage III colon cancer treated with celecoxib: Findings from CALGB (Alliance)/SWOG 80702. Nowak JA, Shi Q, Twombly T, et al. J Clin Oncol. 2025;43(4):LBA14.

Late Breaking Abstract – 2025 ASCO GI Symposium: Personalized Neoantigen Vaccine in Metastatic Colorectal Cancer

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SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 154,270 new cases of CRC will be diagnosed in the United States in 2025 and about 52,900 patients will die of the disease. The lifetime risk of developing CRC is about 1 in 23.

The majority of CRC cases (about 75 %) are sporadic whereas the remaining 25 % of the patients have a family history of the disease. Only 5-6 % of patients with CRC with a family history background are due to inherited mutations in major CRC genes, while the rest are the result of accumulation of both genetic mutations and epigenetic modifications of several genes. Colorectal Cancer is a heterogeneous disease classified by its genetics, and even though the diagnosis of Colorectal Cancer in the US is dropping among people 65 years and older, the incidence has been rising in the younger age groups, with 12% of Colorectal Cancer cases diagnosed in people under age 50.

The DNA MisMatchRepair (MMR) system is responsible for molecular surveillance and works as an editing tool that identifies errors within the microsatellite regions of DNA and removes them. Defective MMR system leads to MSI (Micro Satellite Instability) and hypermutation, with the expression of tumor-specific neoantigens at the surface of cancer cells, triggering an enhanced antitumor immune response. MSI is therefore a hallmark of defective/deficient DNA MisMatchRepair (dMMR) system and occurs in 15% of all colorectal cancers. MSI testing is performed using a PCR or NGS based assay and MSI-High refers to instability at 2 or more of the 5 mononucleotide repeat markers and MSI-Low refers to instability at 1 of the 5 markers. Patients are considered Micro Satellite Stable (MSS) if no instability occurs. MSI-L and MSS are grouped together because MSI-L tumors are uncommon and behave similar to MSS tumors.

Checkpoint inhibitors have revolutionized cancer treatment. They are however not as effective in patients with “cold tumors” (MSS), as these tumors effectively hide themselves from the immune system and do not trigger an immune response following treatment with checkpoint inhibitors.

GRANITE is a personalized neoantigen immunotherapy designed to trigger a strong T-cell immune response against a patient’s tumor. A biopsy of the tumor is performed to identify unique mutations (neoantigens) present in the tumor of patients. An AI platform, EDGE, developed and designed by Gritstone Bio is able to identify critical T-cell vaccine targets, and predict which neoantigens are most likely to be recognized by the immune system of patients. The system has an 80% accuracy rate in selecting the top 20 most immunogenic neoantigens, most likely to generate an immune response in a given patient. The selected neoantigens are incorporated into a chimpanzee adenovirus-based primer vaccine and a Self-Amplifying mRNA (SAM) booster vaccine to train the immune system that leads to an induction of both cytotoxic T-lymphocyte and memory T-cell dependent immune responses, that specifically target and destroy the patients cancer cells that express these neoantigens. This vaccine (GRANITE) is administered via intramuscular injection alongside immune checkpoint inhibitors. Thus GRANITE primes the immune system to recognize and attack these tumors. This vaccine is customized for each patient based on the unique mutations of their tumor. In essence, GRANITE helps make the “cold tumors” visible to the immune system, potentially improving patient outcomes.

GRANITE immunotherapy regimen was evaluated in combination with Nivolumab and Ipilimumab, and compared to the combination of Nivolumab and Ipilimumab alone in a Phase1/2 involving patients with advanced metastatic solid tumors. This study demonstrated robust T-cell activation against targeted neoantigens with no dose-limiting toxicities, and over 50% of patients had a reduction in their circulating tumor DNA (ctDNA) and improved Overall Survival (Palmer CD, et al. Nature 2022).

GRANITE immunotherapy regimen is now being studied as first line metastatic treatment in a randomized Phase 2 trial, among patients with Microsatellite-Stable (MSS) Colorectal cancer patients. GO-010 is an ongoing Phase 2/3, randomized, open-label, multi-center study evaluating the efficacy and safety of GRANITE immunotherapy regimen in combination with Checkpoint Inhibitors (CPIs) as an add-on to Fluoropyrimidine/Bevacizumab as maintenance treatment, following first line therapy with FOLFOX/Bevacizumab, in patients with mCRC. In this study, 104 patients were randomized in a 1:1 ratio, and 67 patients were included in this treated analysis with 39 patients assigned to the GRANITE arm and 28 patients to the control arm. (36 patients withdrew from the study primarily due to early progressive disease or withdrawal of consent, and one patient has yet to begin study treatment). The vaccine manufacturing success rate was 100%. Both treatment groups were well balanced with regards to demographics, clinical characteristics stage, sidedness and presence of liver metastases. Approximately 75% of patients had liver metastases. For the Phase 2 portion of this study, the Primary end point being assessed is molecular response defined as 30% or more decrease from baseline in ctDNA. For the Phase 3 portion of this trial, the Primary end point is Progression Free Survival (PFS). Secondary end points for both Phase 2 and 3 include Adverse Events, Overall Survival (OS), Overall Response Rate (ORR), Duration of Response (DoR) and Clinical Benefit Rate.

Preliminary data from the Phase 2 portion of a Phase 2/3 study showed a positive early trend in PFS for GRANITE immunotherapy patients with a Hazard Ratio (HR) of 0.82 in all patients, HR of 0.52 in high-risk patients1 (more than 90% with liver metastases). The median PFS was 12 months with GRANITE immunotherapy versus 7 months for the control group. Long-term ctDNA responses aligned with positive PFS trend favoring GRANITE immunotherapy patients versus control patients.

In the high-risk group, between first blood draw (time of randomization) and last blood draw (most recent study visit), the ctDNA shifted from high (more than 2% VAF-Variant Allele Frequency) to low (2% or less VAF) in 56% of patients treated with GRANITE immunotherapy versus 22% of control patients. Progressive disease was observed in 44% versus 78% respectively, within this group.

In the low-risk group of patients whose ctDNA was negative after induction chemotherapy, sustained ctDNA negativity was observed in 67% of GRANITE immunotherapy recipients versus 38% in the control patients. Progressive disease was observed in 11% and 38% of these patients, respectively. GRANITE immunotherapy was well tolerated and vast majority of adverse events were Grade1/2 and no patients discontinued study treatment due to an adverse event.

In conclusion, this preliminary Phase 2 results are highly encouraging and suggested that GRANITE immunotherapy demonstrated positive early PFS and long-term ctDNA responses, compared with Fluoropyrimidine/Bevacizumab alone, in front-line metastatic MSS-Colorectal cancer, providing the rationale for a confirmatory Phase 3 trial.

A randomized phase 2 study of an individualized neoantigen-targeting immunotherapy in patients with newly diagnosed metastatic microsatellite stable colorectal cancer (MSS-CRC). Hecht JR, Spira AI, Nguyen AV, et al. J Clin Oncol 43, 2025 (suppl 4; abstr LBA13). DOI 10.1200/JCO.2025.43.4_suppl.LBA13

Late Breaking Abstract – 2025 ASCO GI Symposium: Aspirin Reduces Recurrence in Colorectal Cancer Patients with PI3K Pathway Alterations

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SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 154,270 new cases of CRC will be diagnosed in the United States in 2025 and about 52,900 patients will die of the disease. The lifetime risk of developing CRC is about 1 in 23. Among patients with Stage II-III CRC, 20-40% will develop metastatic disease.

The majority of CRC cases (about 75 %) are sporadic whereas the remaining 25 % of the patients have a family history of the disease. Only 5-6 % of patients with CRC with a family history background are due to inherited mutations in major CRC genes, while the rest are the result of accumulation of both genetic mutations and epigenetic modifications of several genes. Colorectal Cancer is a heterogeneous disease classified by its genetics, and even though the diagnosis of Colorectal Cancer in the US is dropping among people 65 years and older, the incidence has been rising in the younger age groups, with 12% of Colorectal Cancer cases diagnosed in people under age 50.

Aspirin (AcetylSalicylic Acid) has been studied as a chemopreventive agent for several decades and the temporal relationship between systemic inflammation and cancer has been a topic of ongoing investigation. The US Preventive Services Task Force (USPSTF) found adequate evidence that Aspirin use reduces the incidence of CRC in adults after 5-10 years of use, and recommends initiating low-dose Aspirin use for the primary prevention of CardioVascular Disease (CVD) and CRC, in adults aged 50-69 years, who have a 10% or greater 10-year CVD risk, are not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose Aspirin daily for at least 10 years.

Aspirin has been shown to lower the incidence of adenomas and CRC in high-risk patients. Additionally, observational studies suggest that treatment with Aspirin following diagnosis improves Disease-Free Survival (DFS) in unselected populations. Furthermore, retrospective findings indicate that somatic PIK3CA mutations predict treatment response to Aspirin. However this has not been validated in randomized trials.

The ALASCCA trial was designed to find the impact of Aspirin, on the recurrence of CRC with PI3K pathway mutations. The ALASCCA trial is a randomized, double-blind, multicenter, placebo-controlled trial conducted across 33 hospitals in Sweden, Denmark, Finland, and Norway. Researchers screened 3,508 patients diagnosed with Stage II or III colon cancer or Stage I, II, or III rectal cancer and identified 1,103 individuals with PI3K pathway mutations. Participants were categorized into two groups:

• Group A (N=515): Patients with a PIK3CA mutation in exon 9 and/or 20.
• Group B (N=588): Patients with other PI3K mutations, including PIK3CA mutations outside exon 9/20 or mutations in PIK3R1 or PTEN genes.

Of the 626 patients (419 with colon cancer and 207 with rectal cancer) who continued participation in this trial, 157 and 156 patients in Groups A and B respectively, received Aspirin 160 mg daily for 3 years, whereas 157 and 156 patients in each respective group received placebo. The median age was 66 years, 52% of patients were female, and majority of patients were white. Fifty percent of patients with both rectal and colon cancer had received neoadjuvant therapy. The Primary end point was Time to CRC recurrence (TTR). Secondary end points included Disease Free Survival (DFS) in Group A, TTR in Group B, DFS in Group B, and Safety.

The study met its Primary end point and demonstrated that Aspirin use significantly reduced the risk of CRC recurrence. After 3 years of follow up in Group A, patients taking Aspirin had a 51% lower recurrence risk compared to the placebo group (HR=0.49; P=0.044). In Group B, patients taking Aspirin experienced a 58% reduction in recurrence risk versus the placebo group (HR=0.42; P=0.013). Overall, across all groups, Aspirin was associated with a 55% reduced risk of recurrence compared to placebo. There was no statistically significant difference in 3-year DFS rates among those who received Aspirin versus placebo in Group A (88.5% versus 81.4%, respectively; HR=0.61; P =0.091). There was however significantly improved DFS rates in Group B with Aspirin use (89.1% versus 78.7%, respectively; HR=0.51; P=0.17). Severe side effects of daily Aspirin use were rare.

The researchers concluded that this landmark study provides compelling evidence for the role of low-dose Aspirin in reducing colorectal cancer recurrence in patients with PI3K pathway mutations. By integrating precision medicine with a widely available drug, the ALASCCA trial sets the stage for a new standard in colorectal cancer management.

Low-dose aspirin to reduce recurrence rate in colorectal cancer patients with PI3K pathway alterations: 3-year results from a randomized placebo-controlled trial. Martling A, Lindberg J, Myrberg IH, et al. J Clin Oncol. 2025;43(4):LBA125.

Revolutionizing Treatment: Newer Agents and Innovations mCRC Management

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Written by: Dr. Jerome Goldschmidt Jr, MD
Sponsored by Takeda

The treatment landscape for metastatic colorectal cancer (mCRC) has seen considerable evolution over the past two decades. Early therapeutic strategies focused on a handful of chemotherapy agents, with incremental progress in survival seen through the addition of targeted therapies like VEGF and EGFR inhibitors. However, while these agents offered modest improvements, they also brought additional toxicity. More recent advancements, particularly in molecular diagnostics, have ushered in a new era of precision medicine, enabling a better understanding of genetic mutations and the tailoring of treatments. This article examines the key advancements in mCRC management, including immunotherapies, targeted therapies, and chemotherapy agents, and how these innovations are transforming the treatment landscape for this complex disease.

For almost two decades mCRC management has revolved around the use of a handful of drugs: 5-fluorouracil (5-FU), leucovorin, oxaliplatin and irinotecan. Additions to the chemotherapy backbones of FOLFOX and FOLFIRI with the VEGF and EGF receptor inhibitors were the first big innovation in the early 2000s. In retrospect, the benefit of adding these targeted agents to the chemotherapy backbone added on average 2-3 months to overall survival with additional toxicity. It took another few years to discover that EGFR blockers were only effective in ~40% of patients with the discovery of mutated KRAS, BRAF and NRAS. To date, biomarkers pointing to the benefit from VEGF inhibition have proven elusive.

This brings us to newer agents which are now interwoven into the tapestry of more modern molecular diagnostics. Molecular diagnostics have changed some of the paradigms in which mCRC patients are treated currently. These agents can be summarized as follows:

Immunotherapies:
Approximately 15% of CRC patients will be classified as having unstable microsatellites. What this means in practical terms are the addition of repeating, multiple CpG islands in the genome of the malignant colonocytes due to inappropriate mismatch repair mechanisms. A little under half of these MSI high patients will have germline mutations in mismatch repair genes like MLH1, MSH2, MSH6 or PMS2 and often present at an earlier age with CRC as part of the “Lynch Syndrome.” More than half of MSI patients will have acquired this genotype through an apparent random methylation of one of these genes which is more common in cells as they senesce. POLE and POLD1 mutations are another family of mutations involving DNA repair that are implicated in the formation of colorectal cancers. These tumors usually have high tumor mutational burden yet are microsatellite stable. The mismatch repair deficient or MSI high colon cancers as well as the POLE and POLD1 mutants are exquisitely sensitive to immune checkpoint inhibitors.1 First line therapies with single agent pembrolizumab and combination ipilimumab/nivolumab are now standard of care.

Targeted therapies:
HER2 directed therapy has long been employed in the more proximal GI tract. HER2 overexpression has been seen in fewer colorectal cancers. Patients will derive benefit with a trastuzumab backbone and the addition of either pertuzumab, tucatinib or lapatinib. The ADC fam-trastuzumab deruxetecan may be employed upon progression.2

The BRAF inhibitor encorafenib and others have long been a staple in the management of melanoma. In CRC, encorafenib is paired with either of the EGFR blockers, panitumumab or cetuximab to extend the usefulness of these antibodies in what would otherwise be a resistant tumor to EGFR blockade.

KRAS G12C is the most commonly mutated form of the KRAS family and has been found to be safely inhibited with two newer agents, sotorasib and adagrasib. Analogous to encorafenib, they must be paired with one of the EGFR blockers approved in mCRC to overcome resistance to these antibodies.

Chemotherapy:
Trifluridine and tipiracil combination by itself or paired with bevacizumab is approved for third line therapy. Modest improvements in overall survival have been seen. It appears to be agnostic in its mechanism of action as it targets DNA synthesis much like its relatives 5FU and capecitabine. Neutropenia appears to be its dose limiting toxicity.

VEGF inhibitors:
Fruquintinib is a novel oral small-molecule tyrosine kinase inhibitor that selectively targets vascular endothelial growth factor receptors (VEGFR-1, -2, and -3). Its mechanism of action involves the inhibition of VEGF-induced phosphorylation of these receptors, which leads to reduced endothelial cell proliferation, migration, and survival, ultimately inhibiting tumor angiogenesis, and promoting tumor cell death. Approved by the FDA on November 8, 2023 for use in adult patients with refractory metastatic colorectal cancer (mCRC), fruquintinib is indicated for those who have previously undergone treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, as well as anti-VEGF and anti-EGFR therapies if RAS wild-type.3

Clinical trials, including FRESCO and FRESCO-2, demonstrated significant improvements in overall survival rates; patients receiving fruquintinib had a median overall survival of 7.4 months compared to 4.8 months for placebo recipients in the FRESCO-2 trial.4 The recommended dosage is 5 mg orally once daily for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity occurs.5 Common adverse effects include hypertension, palmar-plantar erythrodysesthesia, and proteinuria. This drug represents a critical advancement in the therapeutic landscape for mCRC, particularly in patients who have exhausted other treatment options.

Regorafenib has stood alone for many years as the sole agent in this space. Inhibiting VEGF is the main mechanism of action of this TKI with regards to suppressing colon tumors. It is often used as third line and beyond with only modest benefit. Noteworthy are its significant toxicities at full dose and often requires a ramp up phase to achieve tolerance of the dreaded hand foot syndrome associated with it.

The management of mCRC has made substantial advancements with the introduction of molecular diagnostics and targeted therapies. While the combination of chemotherapy agents and targeted therapies initially provided incremental survival benefits, newer innovations, such as immunotherapies and precision-targeted treatments, are offering more personalized and effective options for patients. However, challenges remain in determining the optimal use of these therapies, managing associated toxicities, and identifying the right biomarkers for treatment selection. As research continues to evolve, the future of mCRC treatment looks increasingly promising, with the potential for even greater advancements in patient outcomes.

Information regarding the studies:
FRESCO – https://jamanetwork.com/journals/jama/fullarticle/2685988
FRESCO2 – https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)00772-9/abstract

References

  1. Ambrosini M, et al. Immune checkpoint inhibitors for POLE or POLD1 proofreading-deficient metastatic colorectal cancer. Ann Oncol. 2023;35(7):643-655.
  2. Strickler JH, Cercek A, Siena S, André T, Ng K, Van Cutsem E, et al. Tucatinib plus trastuzumab for chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer (MOUNTAINEER): a multicentre, open-label, phase 2 study. Lancet Oncol. 2023;24(5):496-508
  3. S. Food and Drug Administration. FDA approves fruquintinib for metastatic colorectal cancer. FDA website. Published November 8, 2023. Accessed January 31, 2025.
  4. Xu RH, Muro K, Morita S, et al. FRESCO-2: A Phase III trial of fruquintinib in patients with refractory metastatic colorectal cancer. Ann Oncol. 2023;34(6):779-787.
  5. Abernero J, et al. Fruquintinib: An oral inhibitor of VEGFR for the treatment of metastatic colorectal cancer. Clin Cancer Res. 2023;29(4):1025-1033.